X-linked adrenoleukodystrophy (ALD) is a relatively common disorder that shows a great deal of phenotypic variability. Approximately half of the patients have the rapidly progressive childhood cerebral form that is associated with an inflammatory response in brain and leads to total disability or death during the first decade. Twenty five per cent or more of the patients have adrenomyeloneuropathy (AMN), a form that progresses slowly, involves the spinal cord mainly, shows little or no inflammatory response, manifests in adulthood, and is compatible with a near-normal life span. The two forms of the disease occur frequently within the same kindreds and nuclear families. Segregation analysis based on 3862 individuals in 89 kindreds points to the existence of an autosomal modifier locus with a likelihood ratio of 20:1. In addition, we present preliminary results of three types of therapy. Two hundred and four patients have received a dietary regimen that combines the administration of oils containing mono-unsaturated fatty acids (oleic and erucic) with the restricted intake of very long-chain fatty acids. This regimen normalizes the levels of satured very long-chain fatty acids in plasma within 4 weeks. It appears to improve peripheral nerve function in patients with AMN, and a large-scale trial is in progress to determine whether it can prevent the onset of neurological involvement in patients who have the biochemical abnormality of ALD but are neurologically intact. We report early results of bone marrow transplantation in 14 patients. There is encouraging but still preliminary evidence that transplantation can arrest the progression of the disease in patients with mild neurological involvement. There is urgent need to develop methods to combat the rapid progression of the cerebral forms of the disease, which so far has resisted therapeutic intervention, including immunosuppression or the administration of immunoglobulin.

Brain, liver, and adipose lipids were studied in the postmortem tissues of four adrenoleukodystrophy patients who had been treated with a mixture of glyceryl trioleate and trierucate oils ("Lorenzo's Oil") and compared to 7 untreated ALD patients and 3 controls. The dietary therapy appeared to reduce the levels of saturated very long chain fatty acids in the plasma, adipose tissue and liver; in the brain they were reduced in only one of the four patients. While substantial amounts of erucic acid were present in some of the tissues even 12 months after therapy had been discontinued, the levels in brain did not exceed those in controls at any time. The failure of erucic acid to enter the brain in significant quantity may be a factor in the disappointing results of dietary therapy for adrenoleukodystrophy.

A new dietary regimen has been administered for periods ranging from 60 days to 1 1/2 years in 34 patients with various forms of X-linked adrenoleukodystrophy (ALD), as well as in 1 patient with neonatal ALD and 1 patient with infantile Refsum's disease. The diet combines the administration of a glyceryl trioleate oil (GTO) with the dietary restriction of very-long-chain fatty acids (VLFA), particularly hexacosanoic acid (C26:0). Reductions in the levels of plasma C26:0 and other VLFA were achieved in 25 of the 36 patients. Fifteen of these 25 patients were treated for more than 100 days. The mean reduction of the plasma C26:0 level was 53% (range, 22 to 73%) in these 15 patients. While the focus of the study was on biochemical variables, comparison of pre- and post-diet studies of peripheral nerve function showed improvement in 1 patient with adrenomyeloneuropathy (AMN) and 1 heterozygote. In contrast, 2 patients with ALD onset in childhood developed new neurological deficits while on therapy. We conclude that it is possible to lower plasma VLFA levels in ALD patients. A clinical trial is indicated to test whether this approach can alter the neurological progression in patients with AMN or in symptomatic heterozygotes, and to determine whether it can prevent the onset of neurological disability in asymptomatic persons who have the biochemical defect of ALD.

Glucose metabolism is altered after trauma and those factors that affect glucose metabolism often affect chromium (Cr) metabolism and excretion. To ascertain whether urinary Cr excretion is affected by the elevated serum glucose and other factors associated with trauma, the serum glucose and urinary Cr and Creatinine (Cre) excretion of seven severely traumatized patients were determined. The Cr concentration of intravenous (IV) fluids administered was determined and approximate Cr intake calculated. For all patients, urinary Cr concentration was high in the initial sample collected within 24 h of admission (10.3 ± 2.5 ng/mL, mean ± SEM) and decreased significantly (P < 0.05) by 42 h (2.0 ±0.6 ng/mL). The mean urinary Cr concentration 42 h following admission was 10 times greater than the urinary Cr concentration of normal, healthy subjects (0.2 ± 0.02 ng/mL). There was no significant change in urinary Cre concentration within 42 h of admission, therefore the ratio of urinary Cr to Cre (ng Cr:mg Cre) also decreased. Serum glucose concentration was elevated at admission (170 ± 18 mg/dL, mean ± SD) and decreased to 145 ± 10 mg/dL by 48 h post-admission. The intravenous fluids, dextrose and NaCl, were the lowest in Cr of the samples tested, range 0.02 to 0.20 ng/mL; lactated Ringer's solution, with or without dextrose, contained 10-20 times more Cr and plasma protein fraction contained approximately 32 ng/mL. The mean calculated Cr intake for the first 24 h postadmission was 37.1 µg/d, significantly greater (P < 0.01) than intake from 24 to 48 h (0.12 µg/d) and 48-72 h (1.63 µg/d). The IV intake of Cr varied for trauma patients depending on fluids required during treatment, but for all patients the relatively high IV Cr intake was rapidly excreted in the urine. These data demonstrate that urinary Cr concentration is elevated several-fold within 24 h of trauma and that Cr contents of intravenous fluids administered in the days immediately following injury vary dramatically. The effects of trauma alone on Cr excretion are difficult to assess because of the variable intake of Cr from IV fluids.

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